It is becoming increasingly appreciated that adipose tissue macrophage activation plays an important role in the development of chronic inflammation and metabolic dysfunction associated with obesity. The status of the vascular cells in adipose tissue has also received recent attention because it can contribute to fat pad dysfunction. Obese organisms display capillary rarefaction and diminished perfusion in their fat pads. Adipose tissue hypoxia is thought promote inflammation because this stress will favor adipocyte necrosis and lead to macrophage recruitment. In turn, the fat pad milieu of an obese organism will favor macrophage activation and lead to further degradation of the vascular bed. Thus, it is reasonable to speculate that obesity favors a vicious cycle of fat pad hypoxia and inflammation in the fat pad. Adiponectin is a fat-derived cytokine that has both anti-inflammatory and pro-angiogenic activities. Adipose tissues from lean organisms express high levels of adiponectin and there is a progressive decline in adiponectin expression as fat mass increases. Both inflammatory cytokines and hypoxia will lead to reductions in adiponectin expression by adipocytes. Published work from my lab has shown that adiponectin will promote endothelial cell function and angiogenesis in a variety of ischemia models, but the role of adiponectin in fat pad vascularization has never been examined. Furthermore, while adiponectin has recognized anti- inflammatory properties, its effect on adipose tissue macrophage polarization has never been systematically delineated. In this proposal, we will perform a series of experiments to investigate the role of adiponectin in fat pad biology to define the functional interrelationship between inflammation and hypoxia in obesity. The proposed experiments will test the hypotheses that adiponectin functions as a direct regulator of macrophage phenotype, favoring anti- inflammatory, M2-like polarization, and that it promotes fat pad perfusion. We propose that these activities of adiponectin control the microenvironment of the fat pad, and thereby influence systemic metabolism and cardiovascular function. Furthermore, gene ablation experiments in vitro and in mouse genetic models will be performed to determine the identities of the receptors that confer adiponectin's actions on fat pad perfusion and inflammation. PUBLIC HEALTH RELEVANCE: Clinical studies have documented that obese individuals differ markedly in their abilities to cope with excess fat tissue or develop a chronic low-grade inflammatory state and insulin resistance. This research will examine how the microenvironment of the fat pad, determined by the status of the vascular bed and composition of inflammatory cells, influences the overall metabolic health of the organism.